A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation
Junya Suzuki, Kosuke Kaji, Norihisa Nishimura, Takahiro Kubo, Fumimasa Tomooka, Akihiko Shibamoto, Satoshi Iwai, Yuki Tsuji, Yukihisa Fujinaga, Koh Kitagawa, Tadashi Namisaki, Takemi Akahane, Hitoshi Yoshiji
Abstract
The renin–angiotensin–aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl4)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl4-induced liver fibrosis while reducing α-SMA+-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl4-treated mice, and ANP effectively suppressed cell proliferation and TGF-β-stimulated MMP2 and TIMP2 expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression of TIMP1 and CTGF through the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis.